Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole

N.G. Anthony, B.F. Johnston, A.I. Khalaf, S.P. Mackay, J.A. Parkinson, C.J. Suckling, R.D. Waigh

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Isopropyl-thiazole (iPrTh) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)2 is bound by a short lexitropsin of sequence formyl-PyPyiPrTh-Dp (where Py represents N-methyl pyrrole, iPrTh represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT5AG7T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the iPrTh group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G7 and the iPrTh nitrogen, which lies on the minor groove floor. The BI/BII DNA backbone equilibrium is altered at the T5 3'-phosphate position to accommodate a BII configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.
LanguageEnglish
Pages11338-11349
Number of pages11
JournalJournal of the American Chemical Society
Volume126
Issue number36
DOIs
Publication statusPublished - 19 Aug 2004

Fingerprint

Thiazoles
DNA
Ligands
Reading Frames
DNA sequences
Hydrophobicity
Hydrophobic and Hydrophilic Interactions
Reading
Pyrroles
Gene Targeting
Nucleic acids
Base Pairing
Nucleic Acids
Amines
Protons
Hydrogen
Hydrogen bonds
Phosphates
Nitrogen
Genes

Keywords

  • short lexitropsin
  • 5'-ACTAGT-3'
  • isopropyl-thiazole
  • ligand binding
  • hydrophobicity
  • gene targeting

Cite this

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title = "Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole",
abstract = "Isopropyl-thiazole (iPrTh) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)2 is bound by a short lexitropsin of sequence formyl-PyPyiPrTh-Dp (where Py represents N-methyl pyrrole, iPrTh represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT5AG7T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the iPrTh group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G7 and the iPrTh nitrogen, which lies on the minor groove floor. The BI/BII DNA backbone equilibrium is altered at the T5 3'-phosphate position to accommodate a BII configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.",
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Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole. / Anthony, N.G.; Johnston, B.F.; Khalaf, A.I.; Mackay, S.P.; Parkinson, J.A.; Suckling, C.J.; Waigh, R.D.

In: Journal of the American Chemical Society, Vol. 126, No. 36, 19.08.2004, p. 11338-11349.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole

AU - Anthony, N.G.

AU - Johnston, B.F.

AU - Khalaf, A.I.

AU - Mackay, S.P.

AU - Parkinson, J.A.

AU - Suckling, C.J.

AU - Waigh, R.D.

PY - 2004/8/19

Y1 - 2004/8/19

N2 - Isopropyl-thiazole (iPrTh) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)2 is bound by a short lexitropsin of sequence formyl-PyPyiPrTh-Dp (where Py represents N-methyl pyrrole, iPrTh represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT5AG7T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the iPrTh group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G7 and the iPrTh nitrogen, which lies on the minor groove floor. The BI/BII DNA backbone equilibrium is altered at the T5 3'-phosphate position to accommodate a BII configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.

AB - Isopropyl-thiazole (iPrTh) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)2 is bound by a short lexitropsin of sequence formyl-PyPyiPrTh-Dp (where Py represents N-methyl pyrrole, iPrTh represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT5AG7T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the iPrTh group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G7 and the iPrTh nitrogen, which lies on the minor groove floor. The BI/BII DNA backbone equilibrium is altered at the T5 3'-phosphate position to accommodate a BII configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.

KW - short lexitropsin

KW - 5'-ACTAGT-3'

KW - isopropyl-thiazole

KW - ligand binding

KW - hydrophobicity

KW - gene targeting

UR - http://dx.doi.org/10.1021/ja030658n

U2 - 10.1021/ja030658n

DO - 10.1021/ja030658n

M3 - Article

VL - 126

SP - 11338

EP - 11349

JO - Journal of the American Chemical Society

T2 - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 36

ER -